tbuckley/cabot-search huggingface dataset:
Abstract 5024: Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin
Authors: Mahfuza Marzan, Nuzhat Nowshin Oishee, Khandker Mohammad Khalid, Mildred Acevedo-Duncan
Journal: Cancer Research (2023)

Abstract Ovarian cancer causes more death than any other cancers of the female reproductive system. Current treatment strategies are surgical removal of cancerous parts and chemotherapy with platinum drugs (e.g. cisplatin, carboplatin) or taxols. However, recurrence of cancer with drug resistance is frequent. Previously two inhibitors; ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and ζ-stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid) specific for two atypical protein kinases, PKC-ι and PKC-ζ respectively have been reported. These inhibitors have an anticancer effect in different cancers, including clear-cell ovarian cancer. Our aim was to find if cisplatin has any synergistic effect with ICA-1S and ζ-stat on ovarian cancer cell proliferation, migration, and apoptosis. Ovarian cancer cell line ES-2, which has mutation in p53 gene was used in this study. After 72 hours of treatment with ICA-1S (10 µM) and ζ-stat (10 µM), proliferation of ES-2 cell line was inhibited by 42.5% and 23.5% respectively compared to control. When combined with cisplatin (0.5 µM), the inhibition of cell proliferation increased to 67% for ζ-stat and 65.8% for ICA-1S (N=3 trials) which is synergistic. Wound healing assay with ES-2 cells showed that ICA-1S and cisplatin inhibited the migration of ES-2 cells separately as well as in combination. SDS-PAGE and subsequent western blotting showed that ICA-1S monotherapy and combination with cisplatin reduced the expression mutant p53, PI3K, AKT, Bcl2, and phopho-BAD. IP with PKC ζ beads showed the association of PKC ζ with PKC-ι and p53 in ES-2 cell line. As mutation in p53 is quite frequent in ovarian cancer with gain of function, ICA-1S may have an advantageous role in inhibiting mutated p53 regulated pathway. Inhibition of ES-2 cell line with ICA-1S and ζ-stat also suggested that PKC-ι and PKC ζ play important roles in ovarian cancer and may augment traditional chemotherapy. Further study on the pathway affected by aPKC inhibitors combined with cisplatin would be investigated through WST, western blotting and immunoprecipitation assay. Citation Format: Mahfuza Marzan, Nuzhat Nowshin Oishee, Khandker Mohammad Khalid, Mildred Acevedo-Duncan. Role of protein kinase C ζ and ι inhibitors on ovarian cancer cell lines in combination with cisplatin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5024.
Abstract 4097: Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas
Authors: Lauren Kelsey, Karin Latta, Joey Kolb, Bincy John, Ilona Aylott, Daniel Rocca, Alexandru Bacita, Christopher Kirkham, Patrick Walters, Charlotte Humphery, Lorena Sueiro Ballesteros, Jezrom Self-Fordham, Louise Brackenbury, Chassidy Hall, Harris David, Julia Schueler, Robert Nunan
Journal: Cancer Research (2023)

Abstract Chimeric Antigen Receptor (CAR)-T cell therapy has achieved great success in treating a variety of liquid tumors, in particular CD19+ lymphomas. CAR technology is advancing rapidly, with notable improvements in efficacy, safety and complexity as human ingenuity seeks solid tumor applicability. Here we describe how to efficiently generate, expand and validate in-vitro and in-vivo efficacy of a clinically tested CD19-specific CAR. HLA-A*02:01+ CD3+ T-cells were transduced to express a CD19-CAR to &amp;gt;80% efficiency (in 5 donors) and reproducibly expanded to &amp;gt;68 fold over a 19 day period. In-vitro studies were used to assess tumor killing ability, utilizing a HLA-A*02:01+ patient derived xenograft (PDX) CD19+ cell line, alongside human cancer cell lines RAJI (CD19+) and K562 (CD19-). Analysis revealed the potent ability of CD19-CAR-T cells to specifically target CD19+ cells in a dose dependent manner. Supernatant analysis showed highly elevated IFNγ concentrations, identifying enhanced activation of CAR-T cells in the presence of CD19+ target cells only. In-vivo survival studies were completed to identify translatability &amp; efficacy in both systems. Mice were inoculated with CD19+ cells to produce multiple tumor burdened models (RAJI, JEKO-1 &amp; PDX4009). This demonstrated high efficacy of CAR-T at targeting both tumor cell line RAJI or PDX in vivo, with almost complete tumor regression seen in both models. JEKO-1 tumors saw progression slowed in comparison to non-transduced or no treatment controls however due to the nature of this cell line (highly tumorigenic) the level of tumor regression was not matched to the other models. Cell bio-distribution was assessed with CAR-T cells tracking successfully to the tumors as well as the highly vascularized tissues, which was expected and consistent with previous data. These assays can be translated to any CAR construct aimed at targeting either solid or hematological tumors and demonstrates an integrated platform for translating CAR research that can be utilized end to end. Citation Format: Lauren Kelsey, Karin Latta, Joey Kolb, Bincy John, Ilona Aylott, Daniel Rocca, Alexandru Bacita, Christopher Kirkham, Patrick Walters, Charlotte Humphery, Lorena Sueiro Ballesteros, Jezrom Self-Fordham, Louise Brackenbury, Chassidy Hall, Harris David, Julia Schueler, Robert Nunan. Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4097.
Abstract 4141: Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model
Authors: Joseph P. LaMorte, Brittany Tian, Rashida Ginwala, Laura Bukavina, Philip Abbosh
Journal: Cancer Research (2023)

Abstract Recent studies have begun to demonstrate the therapeutic capacity of physical exercise on cancer treatment outcomes. While this research suggests exercise may improve health in cancer patients, the specific mechanisms by which exercise influences tumor progression remain largely unknown. We hypothesized that exercise alters the gut microbiome and promotes immune cell activation in relevant immune sites. Therefore, we utilized BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine), a carcinogen that mimics human muscle invasive bladder cancer conditions, and voluntary exercise wheels to determine the effect of exercise on bladder carcinogenesis, gut microbiome, and the immune system. Ultrasound imaging revealed that the average tumor volume of female exercising mice was 11.9% of the total bladder volume at time of sacrifice, while the tumor volume of their non-exercising counterparts was 56.4%, a difference determined to be significant using a two-tailed t-test with p-value of 0.05. A similar trend was seen in male mice, though the difference between groups was not significant. Immune cell analysis did not show significant variation in cytotoxic T cell, helper T cell, macrophage, or dendritic cell populations between exercising and non-exercising mice in spleen, colon, or bladder tissues as measured by FACS. Standardization of the amount exercised, as evaluated by expression of myosin and actin levels in the tibialis anterior muscle, and sequencing of the gut microbiome are in progress and could better indicate the mechanism of exercise-induced tumor suppression. Citation Format: Joseph P. LaMorte, Brittany Tian, Rashida Ginwala, Laura Bukavina, Philip Abbosh. Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4141.
Abstract 2560: Post-translational modification of focal adhesion kinase (FAK) protein increases in breast cancer cells upon exposure to conditioned medium derived from in vitro and in vivo adipocytes
Authors: Noshin Mubtasim, Caleb Boren, Benjamin Barr, Lauren Gollahon
Journal: Cancer Research (2023)

Abstract Under obese conditions, dysregulation of the normal secretion of adipokines from fat cells has been shown to drive cancer progression. However, the role adipokine dysregulation plays in driving metastasis is still unclear. Recent studies have reported the activation of metastasis-associated cell signaling pathways. One such pathway involves Focal Adhesion Kinase (FAK), a non-receptor cytoplasmic protein that acts as a signal transducer between receptor activation by adipokines and downstream effector proteins that control the biological phenomenon of metastasis. Nevertheless, the association between obesity-induced changes in adipocyte secretory factors and the subsequent increase in the transactivation of FAK through phosphorylation is unknown. To elucidate the potential relationship of adipocyte-secreted factors towards activating FAK, breast cancer cells with low (MCF7) and high (MDA-MB-231) metastatic potential were exposed to in vitro and in vivo, murine adipocyte-derived, conditioned medium. For the in vitro adipocyte model, 3T3-L1 MBX cells differentiated to obesity, with fatty acids supplementation, were used. For the in vivo model, adipocyte-secreted factors from organ-cultured visceral fat harvested from C3H/HeJ female mice fed an either high fat (46%) or control (11%) diets, were collected in the medium. Adipocyte secretions from the in vitro and in vivo adipocyte samples were determined using a mouse adipokine proteomic profiler array and ELISA kit. Under obese conditions, both the 3T3-L1 MBX cells and C3H/HeJ visceral fat were found to have significant changes in their adipokine secretions in comparison to controls. Results showed that the breast cancer cells got increased FAK autophosphorylation when exposed to either in vitro or in vivo-derived obese adipocyte-conditioned medium in comparison to the untreated breast cancer cells. Citation Format: Noshin Mubtasim, Caleb Boren, Benjamin Barr, Lauren Gollahon. Post-translational modification of focal adhesion kinase (FAK) protein increases in breast cancer cells upon exposure to conditioned medium derived from in vitro and in vivo adipocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2560.
Abstract 4981: The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in <i>in vitro</i> and <i>in vivo</i> models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC
Authors: Nicole Williams, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2023)

Abstract The compound QN-302, a tetra-substituted naphthalene diimide (ND) derivative has been designed to have high affinity for G-quadruplex (G4) nucleic acids. It has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and anti-tumor activity in xenograft, orthotopic and genetic (KPC) models for pancreatic cancer (PDAC). Its mode of action involves the targeting of G4-forming sites in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. Transcriptome analyses of QN-302 in MIA-PACA2 cells have confirmed genes involved in cancer-associated pathways and carry G4 motifs in their promoters as targets. We have found that expression of the S100P gene, a well-authenticated indicator of PDAC disease and progression, is highly down-regulated in QN-302 treated cells. The S100P gene contains at least five putative G4 motifs, including a classic G4 promoter site just upstream of the transcription start site. We have observed that transcriptome analyses on tumor material from human PDAC patients, and those from poorly differentiated as well as more highly differentiated tumors, have shown that the S100P gene is highly over-expressed (especially in poorly differentiated tumors). We now report on gene expression analysis of S100P using control and treated tumor tissues from a therapeutic study in PDAC MIA-PACA2 xenografts in mice, by means of RT-qPCR and Western blot analyses. The data shows statistically significant dose-dependent decreases in expression of S100P at both the mRNA (to ca 25% of control values) and protein levels (to ca 22% of control values), giving added confidence to the concept that the S100P gene is a therapeutic target in PDAC and may also be useful as a marker of QN-302 response in future clinical use. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in the animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage. Citation Format: Nicole Williams, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4981.
Abstract 2353: PTGES is involved in the myofibroblast differentiation
Authors: Yi-Fang Yang, Yi-Chen Lee, Min-Hsi Lin
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related death worldwide, and patients usually have poor prognoses and low 5-year survival rates. Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both chronic and dysfunction of lung refers to lung fibrosis and increased risk of lung cancer. Myofibroblasts contribute to the procession of asthma, COPD, and IPF, leading to fibrosis of the airway and lung. Accumulating evidence has shown metabolic reprogramming has been considered a major hallmark of fibrosis and plays an important role in the fibrosis process. In this study, we identified Prostaglandin E Synthase (PTGES) was upregulated in lung fibroblast after being treated with IL-4, IL-13, and TNF-α, respectively. We found that PTGES increased the levels of myofibroblast markers α-SMA, FAP, and Vimentin, and promoted lung fibroblast cell migration and invasion. Further, in vivo lung fibrosis model demonstrated that PTGES was upregulated in lung fibrosis rats. PTGES induces phosphorylation of ERK1/2 and HIF-1α expression in lung fibroblast cells. Based on our findings, PTGES increases the expression of myofibroblast markers to modulate the myofibroblast differentiation. Citation Format: Yi-Fang Yang, Yi-Chen Lee, Min-Hsi Lin. PTGES is involved in the myofibroblast differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2353.
Abstract 1246: Single-cell profiles of multiplexed <i>in vivo</i> models facilitate the characterization of phenotypic plasticity and invasion in glioblastoma
Authors: Toshiro Hara, Rony Chanoch-Myers, Alissa Greenwald, Lillian Bussema, Jinan Behnan, Rossella Galli, Hiroaki Wakimoto, Itay Tirosh, Mario Suvà
Journal: Cancer Research (2023)

Abstract The lethality of glioblastoma and the failure of surgical treatment are in part attributable to the invasive properties of this cancer; however, our understanding of the cell-biological process is limited due to the complex representation of invasion phenotype in glioblastoma models. Here, to overcome this limitation, we developed an in vivo approach with human glioblastoma spheroid lines multiplexed for mouse intracranial xenografts. We validated this with 20 patient-derived models and identified, by 3’end single-cell RNA-sequencing (scRNA-seq) coupled with deconvolution analysis, in vivo models capable of infiltrating along the periphery of either neurons or blood vessels. We previously found that the diverse malignant cells in glioblastoma specimens exist in a limited set of four cellular states: neural progenitor-like (NPC-like), oligodendrocyte progenitor-like (OPC-like), astrocyte-like (AC-like), and mesenchymal-like (MES-like), with potential for state plasticity under the influence of tumor microenvironment. To determine whether or not the cell state heterogeneity is implicated in glioblastoma invasion, we profiled and characterized programs, states, and clonality of invading glioblastoma cells by comparing cells from the contralateral invasive edge to their counterparts residing at the original bulk tumor. This analysis showed evidence of a bi-directional state transitioning model for cells undergoing distinct environmental spaces. Exploration of cell state distribution at the primary tumors revealed that presence of an OPC-like state was significantly associated with invasion phenotype regardless of the infiltration routes. Our results suggest that cellular plasticity may be a prerequisite for the topographically diffusive nature of glioblastoma, urging further assessment by perturbing critical regulators of the cellular state programs. In conclusion, this work describes multiplexed in vivo models as an enabling platform for the rapid interrogation of patient-derived xenografts, coupling the molecularly measurable states with functional identity driving malignant phenotypes such as cancer invasion. Citation Format: Toshiro Hara, Rony Chanoch-Myers, Alissa Greenwald, Lillian Bussema, Jinan Behnan, Rossella Galli, Hiroaki Wakimoto, Itay Tirosh, Mario Suvà. Single-cell profiles of multiplexed in vivo models facilitate the characterization of phenotypic plasticity and invasion in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1246.
Abstract 2343: Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma
Authors: Jun Ren, Zohreh Amoozgar, Yuhui Zhao, Pinji Lei, William W. Ho, Sylvie Robergea, Peigen Huang, Dan G. Duda, Lei Xu, Rakesh K. Jain
Journal: Cancer Research (2023)

Abstract Ependymoma is a common type of brain tumor in children, often resistant to available cytotoxics. Molecular profiling studies have led to a better understanding of ependymoma pathology and revealed a critical role of EPHB2. However, the immune system's role in tumor progression and treatment response remains poorly understood. Here, we show that the multikinase inhibitor dasatinib potently inhibits EPHB2 and ABL1 and the growth of ependymoma both in vitro and in vivo. Using an immunocompetent mouse model of ependymoma that faithfully recapitulates its immune microenvironment, we found an increased frequency of M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size. Treatment with dasatinib reprogrammed the immune microenvironment of ependymoma by polarizing the TAMs toward an M1-like phenotype and increasing CD8 T cell activation. Dasatinib treatment induced complete regression of established mEPN-Ephb2 tumors in 78% of the animals and protected survivors against tumor recurrence. These studies indicate that dasatinib may be an effective therapy for this molecular subgroup of pediatric brain tumors and should be tested in clinical trials. Citation Format: Jun Ren, Zohreh Amoozgar, Yuhui Zhao, Pinji Lei, William W. Ho, Sylvie Robergea, Peigen Huang, Dan G. Duda, Lei Xu, Rakesh K. Jain. Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2343.
Abstract 3978: The growth inhibitory effect of MDV3100 on hormone receptor-positive, HER2-negative breast cancer cell lines with low DYRK2 expression
Authors: Yoshimi Imawari, Rei Mimoto, Kiyotsugu Yoshida
Journal: Cancer Research (2023)

Abstract Introduction: Tumor progression is the main cause of death in patients with breast cancer. Accumulating evidence suggests that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. Recently, we reported for the first time that DYRK2 inhibits breast cancer stem cells and tumor cell proliferation through transcriptional downregulation of KLF4 and CDK14, respectively.Our previous study showed that Androgen receptor (AR) was a DYRK2-dependent transcriptional activator. In this context, we hypothesized that MDV3100, an inhibitor of AR, may be effective for breast cancer with low DYRK2 expression. Methods: We established stable DYRK2-depleted cells. MCF-7 cells, hormone receptor-positive, HER2-negative breast cancer cell line, were transfected with pSuper-puro vector (pSuper control) or pSuper-puro DYRK2 shRNAs (shDYRK2) along with puromycin to isolate stable cell lines.These manipulated cells were compared with the control cells by various assays. We analyzed the activity of AR by Androgen receptor reporter assay. MTS assays were used to assess growth inhibition after treatment with MDV3100. Results: Androgen receptor reporter assay showed that knocking down DYRK2 induced AR transcription activity in MCF-7 cells.In MCF-7 DYRK2-depleted cells, MTS assays revealed that the treatment by MDV3100 was more effective than that in MCF-7 control cells. Conclusion: These findings demonstrate that reduced DYRK2 expression in hormone receptor-positive, HER2-negative breast cancer increases the activity of AR and significantly inhibits the growth by treatment with MDV3100. Citation Format: Yoshimi Imawari, Rei Mimoto, Kiyotsugu Yoshida. The growth inhibitory effect of MDV3100 on hormone receptor-positive, HER2-negative breast cancer cell lines with low DYRK2 expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3978.